Management of CMV infection and disease in transplant patients. 27-29 February 2004

The International Herpes Management Forum (IHMF) has published guidelines for the diagnosis and management of cytomegalovirus (CMV) infection and disease in solid organ (SOT) and haematopoietic stem cell transplant (HSCT) recipients. These recommendations have been updated to include, among others: (1) use of whole blood for the polymerase chain reaction (PCR) diagnosis of CMV infection; (2) CMV load measurements for prognostication and for monitoring response to anti-CMV therapy; (3) valganciclovir prophylaxis in CMV donor-positive/recipientnegative (D+/R-) SOT patients for prevention of CMV disease; (4) oral ganciclovir prophylaxis, in preference to aciclovir, to reduce incidence of CMV disease in SOT patients; (5) pre-emptive therapy with oral ganciclovir to reduce incidence of CMV disease and viraemia in liver transplant patients; (6) valaciclovir prophylaxis, in preference to high-dose oral aciclovir, to prevent CMV infection in allogeneic HSCT patients; and (7) foscarnet as an alternative to intravenous ganciclovir for pre-emptive treatment of CMV infection in allogeneic HSCT patients. New developments in the field requiring further research were highlighted, including: optimal frequency of CMV monitoring in CMV D+/R- SOT patients; optimal duration of prophylaxis for the prevention of late CMV disease; need for an acceptable viral threshold for initiation of pre-emptive therapy; and assessment of the clinical efficacy of valganciclovir for the treatment of CMV disease and as pre-emptive therapy in SOT and HSCT patients. This article presents supporting evidence for these recommendations and statements.     

How can the evaluation of genetic tests be enhanced? Lessons learned from the ACCE framework and evaluating genetic tests in the United Kingdom.

Advances in genetic technology are increasing the availability of genetic tests, not only for rare single gene disorders, but also for common diseases such as breast and colo-rectal cancer. Before there can be widespread uptake of these tests, they must be evaluated to confirm the benefits of their use. But how should genetic tests be evaluated, given the speed at which new tests are emerging? One highly influential approach is the analytic validity, clinical validity, clinical utility and ethical, legal and social issues (ACCE) framework, which has provided a benchmark for the evaluation of genetic tests. The approach has been adopted and adapted by the United Kingdom Genetic Testing Network, with the help of the Public Health Genetics Unit in Cambridge, to evaluate new genetic tests for use in the National Health Service. We discuss a number of conceptual, methodological, and practical issues concerning the evaluation of genetic tests, based on lessons learned from applying the ACCE framework and from the UK experience, and make a number of recommendations to further strengthen the evaluation of genetic tests.     

Three-year durability of dual-nucleoside versus triple-nucleoside therapy in a Thai population with HIV infection

We compared the long-term immunologic and virologic efficacy of the dual- and triple-nucleoside therapy for HIV infection. This was a retrospective analysis of 2 randomized clinical trials in antiretroviral-naive patients. In the dual-nucleoside group, 15 started with didanosine (ddI) monotherapy and then added stavudine (d4T) after 24 weeks, 63 started with various doses of d4T and ddI, and 53 started with zidovudine (ZDV) and lamivudine (3TC). In the triple-nucleoside group, 53 started with ZDV, 3TC, and ddI. After 48 weeks, patients who were not failing were randomized to immediate (before treatment failure) versus delayed (at the time of virologic failure) switching from ddI and d4T to ZDV and 3TC or vice versa and from ZDV, 3TC, and ddI to d4T, 3TC, and abacavir (ABC). Failure was defined as a plasma HIV-1 RNA level>or=1 log10 above nadir or >or=10,000 copies/mL when nadir was <500 copies/mL. Patients failing therapy before week 48 received the new treatment as in the immediate switching group. Hydroxyurea was added to the last treatment regimen if patients failed after week 96. CD4 count and plasma HIV-1 RNA level (branched DNA assay with a cutoff point of 50 copies/mL) at week 144 were analyzed by intention to treat. Compared with the dual-nucleoside group, the triple-nucleoside group had a higher proportion of patients with <50 copies/mL at 144 weeks (60% vs. 18%; P<0.001), higher median CD4 count (388 cells/microL vs. 346 cells/microL; P=0.018), and longer duration of response, defined as the time from onset of viral suppression (<500 copies/mL) to the time of treatment failure (the first of 2 consecutive HIV-1 RNA measurements >500 copies/mL never followed by 2 consecutive visits showing suppressible viremia to <500 copies/mL) or discontinuation from the study (144 weeks vs. 104 weeks; P=0.002). Multivariate regression analyses showed that significant predictors for treatment success, defined as a plasma viral load <50 copies/mL at week 144, were asymptomatic clinical status at enrollment, a baseline plasma viral load 相似文献   

Problematic Methods in the Assessment of Scholarly Productivity in Clinical PhD Programs

We review the methods in the ranking of clinical psychology doctoral programs provided by Stewart, Roberts, and Roy (2007). Using our own program as an example, we identify several areas of concern (e.g., authorship credits, criteria applied, faculty attrition). The inaccuracies identified for our program ranking, in combination with methodological concerns highlighted by previous commentaries, suggest that the validity of the rankings can be called into question.     

Microglia are more susceptible than macrophages to apoptosis in the central nervous system in experimental autoimmune encephalomyelitis through a mechanism not involving Fas (CD95)

Morphological studies have shown that macrophages and microglia undergo apoptosis in the central nervous system (CNS) in acute experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. To assess the relative levels of macrophage and microglial apoptosis, and the molecular mechanisms involved in this process, we used three-colour flow cytometry to identify CD45lowCD11b/c+ microglial cells and CD45highCD11b/c+ macrophages in the inflammatory cells isolated from the spinal cords of Lewis rats 13 days after immunization with myelin basic protein (MBP) and complete Freund's adjuvant. Simultaneously, we analyzed the DNA content of these cell populations to assess the proportions of cells undergoing apoptosis and in different stages of the cell cycle or examined their expression of three apoptosis- regulating proteins, i.e. Fas (CD95), Fas ligand (FasL) and Bcl-2. Microglia were highly vulnerable to apoptosis and were over-represented in the apoptotic population. Macrophages were less susceptible to apoptosis than microglia and underwent mitosis more frequently than microglia. The different susceptibilities of microglia and macrophages to apoptosis did not appear to be due to variations in Fas, FasL or Bcl- 2 expression, as the proportions of microglia and macrophages expressing these proteins were similar, and were relatively high. Furthermore, in contrast to T cell apoptosis, apoptosis of microglia/macrophages did not occur more frequently in cells expressing Fas or FasL, or less frequently in cells expressing Bcl-2. These results indicate that the apoptosis of microglia and CNS macrophages in EAE is not mediated through the Fas pathway, and that Bcl-2 expression does not protect them from apoptosis. Expression of FasL by macrophages and microglia may contribute to the pathogenesis and immunoregulation of EAE through interactions with Fas+ oligodendrocytes and Fas+ T cells. The high level of microglial apoptosis in EAE indicates that microglial apoptosis may be an important homeostatic mechanism for controlling the number of microglia in the CNS following microglial activation and proliferation.      

The total artificial heart as a bridge to transplantation. A report of two cases

In 1985, at the University of Arizona, Tucson, two attempts were made to "bridge" patients from impending death to heart transplantation, using orthotopically positioned total artificial hearts. The first attempt, using an unapproved device on an emergency basis, failed after transplantation because of severe pulmonary edema and Pseudomonas pneumonia and the apparent transmission of a Pseudomonas infection from donor to recipient. The second experience, using a Jarvik-7 device, led to stable support for nine days with one major complication, a reversible neurologic deficit with no associated computed tomographic scan abnormality. This patient survived cardiac transplantation and, after being successfully treated for complications, has made a full recovery and returned to full-time work.